This is a proposal for continued funding of a 14 year old program project which has been successful in integrating the basic research expertise of this Institution in the areas of Immunology and Biochemistry, with the clinical divisions of Allergy and Autoimmunity. The focus is to clarify mechanisms of disease in hypersensitivity and autoimmunity using immunologic, biochemical and molecular approaches. The program is divided into six projects. Project I examines the role of tissue kallikrein in asthma and is targeted at studies on bronchoalveolar lavage fluid. The identity and source of glandular kallikrein will be determined including its possible role in generating lipid metabolites, leukotrienes and platelet-activating factor. The second project extends earlier studies on the importance of IgE Fc receptors on monocytes, macrophages, eosinophils and platelets in allergy, with special emphasis on aspirin-sensitive asthma. The third project is on sulfite-sensitivity asthma, an allergic disease under special study in this Institution for several years. Mediators resulting from activation of arachidonate, complement and contact systems will be examined to elucidate the mechanism and the role of sulfite oxidase deficiency as well as non-enzymatic catalysis of sulfite oxidation will be studied. The fourth project will study activation of the contact system in angioedema and urticaria, including acquired C1 inhibitor deficiency where a degradation product of C1inh has been shown to be a unique feature. The role of the contact system is evident in the presence of C1inh-kallikrein complexes in plasma and blister fluid. The fifth project involves the isolation, and biochemical and functional characterization, of interleukin-1 (IL-1) inhibitors in various tissue fluids. IL-1 inh released spontaneously from peripheral cell cultures of patients with rheumatoid arthritis following EBV infection, will be an important source of this material. Project VI studies autoimmunity caused by drugs such as procainamide, where the immune response is uniquely restricted to anti-histone antibodies. Monoclonal antibodies to histones will be used to elucidate the nature of the antigenic epitopes and presence of nucleohistones in extranuclear compartments will be examined as part of a study to elucidate this autoimmune phenomenon.